Modeling targeted delivery of biomimetic polymer vesicle gene therapy to cancer

The aim of the project is to assess the feasibility of using nanoparticles to deliver chemotherapeutic drugs to cancer cells. The nanoparticles are synthetic and designed to encapsulate drugs and carry specific markers that target toxic effects efficiently to the tumour cells while protecting other tissues, and thus reducing systemic toxicity. The nanoparticles in question differ to other synthetic delivery devices in terms of their greater loading capacity, improved drug retention and better targeting efficiency. The biggest challenge in their design, however, is how to optimize their specificity of action.We will develop novel mathematical models to tackle this issue. We will use the latest modeling techniques to discover how infiltration, targeting and uptake of the nanoparticles are regulated by their size, mechanical, chemical and membrane properties. Data generated from in vitro lab experiments with the head and neck cancers will be used to inform the mathematical approach for parameterisation and validation. We will then extend the validated models to predict the therapeutic effect in tumours in vivo, focussing on tumours that have acquired a blood supply and developing a model framework which will help focus an in vivo experimental program before animal studies begin. This will permit the investigation of different experimental situations which are technically difficult and the collection of data limited, at a minimum of cost and use of animal models. These targeting issues are relevant to the delivery field in general so our model will also act as a framework for targeted delivery for other tumours as well as other pathologic conditions. The aims of the project are:(i) To develop novel mathematical models of ligand-receptor binding of nanoparticles to cancer cells to predict how targeting can be enhanced by modulating the numbers of ligands and 'stealth' particles on the nanoparticles.(ii) To use data generated from cancer cell culture experiments to parameterise and validate the mathematical models and assess infiltration and delivery patterns in cell populations andidentify conditions of non-specific and actual targeting.(iii) To develop spatio-temporal partial differential equation models to make predictions about nanoparticle stability and therapeutic efficiency given different particle sizes, fluidity and membrane properties and different loads and combinations of cytotoxic drugs with different hydrophobic-hydrophilic properties.(iv) To modify the mathematical models to determine whether acidic tumour conditions can trigger premature release of the vesicle contents.(v) To utilize the mathematical models to inform in vivo experimentation by generating testable hypotheses for determining therapeutic efficiency.

One quarter of the population eventually develops cancer and the social (e.g. a reduced quality of life and life expectancy) and economic costs (e.g. medical costs and loss of earnings) are considerable. In monetary terms for the care of cancer patients, it is estimated that by 2012, we will see an above 200% increase to today's costs in caring for cancer patients (e.g. see Sikora, K., Cancer drugs - the economic challenge, Focus on Oncology, May 2008). Improvements in the treatment outcomes for some solid tumours have reached a plateau despite advances in surgery, chemo- and radio-therapy. Gene therapy offers the timely hope of a new and efficient tool for treating such diseases but safety concerns (including the possibility of inducing severe systemic toxicity) and efficacy has so far prevented a major breakthrough. Synthetic, self assembling biomimetic polymer vesicles (BPVs) are a completely new technology with the advantage that they can be used as ideal targetting delivery systems. This study will help shed insight into whether BPVs are able to significantly better deliver treatment than conventional forms of therapy. Furthermore, because of the flexibility of BPV design and chemical makeup, this work will pave the way to develop targeted delivery agents to a whole range of other pathologic conditions. The project will provide the PDRA with detailed training in the use of mathematical modelling to understand and make predictions for biological systems. The project depends crucially on model development and refinement using experimental data, in collaboration with experimentalists. The resulting models will then be solved using analytical and numerical techniques, teaching a range of methods including perturbation theory, stability analysis and bifurcation theory and providing training in writing numerical codes and in efficient numerical simulation. The PDRA will benefit from the thriving research environments at Strathclyde and Sheffield. Strathclyde has active research programmes in Mathematical Biology (including research into neurological and cardiovascular disorders, blood cell morphology, epidemiology, marine science, medical devices and tissue bioengineering) and the regular seminars and workshops will enable the PDRA to interact with other senior researchers and thus gain a broad training in Mathematical Biology. Dr Craig Murdoch's (CM; see Section 4 of Description of Proposed Research) group has expertise in the bioengineering, chemistry, pathology and clinical aspects of tumour targetting. The consequent active, interdisciplinary research environment will be highly beneficial to the PDRAs career development. Additionally, the University of Strathclyde provides excellent training for PDRAs in the development of generic skills and competencies and thereby widen their scope for future employability. SDW's long term goal is to become a future leader in mathematical biology, with a focus on drug development. A key component of this progress is to establish a research group in mathematical biology which is at the forefront of developing models that can make quantitative, testable predictions about real patients. SDW is already supervising a PhD student on a project which is directly related to the proposal. The EPSRC first grant will provide the core support required to expand this group and make the most of the research opportunities of EPSRC's development programmes, including senior research fellowships and large programme grants. Furthermore, the proposed project involves a strong interaction with leading experimentalists ensuring that SDWs research lies at the forefront of the latest biological developments.